We first compared the inflammatory infiltrates in tissues harvested from patients with severe periodontitis and associated tissue damage to that in tissues with minimal inflammation. Periodontitis lesions were found to be abundantly populated by Th17, cells linked to infection, chronic inflammation, autoimmunity and pathology. These findings expand previous clinical studies demonstrating high levels of IL-17 cytokine in the sera and tissues of patients with periodontitis 27 12. Expression of the signature Th17 cytokine IL-17 as well as the Th17 supporting cytokines IL-1, IL-6 and IL-23 was also significantly higher in diseased lesions. Importantly expression of IL-17 correlated with increased tissue damage (Figure 1). We found that interaction of P. gingivalis with myeloid APCs promoted Th17 differentiation. P. gingivalis stimulated production of cytokines linked to Th17 polarization, and not Th1 related cytokines. Accordingly, when supernatants from myeloid cells stimulated with P. gingivalis were added to PBMC, they supported the differentiation of T cells into Th17 but did not influence Th1 differentiation. P. gingivalis expresses a number of virulence factors, including its LPS and fimbria, which signal through TLR receptors, thus activating NFB-dependent proinflammatory pathways in innate cells 20, 28, 29. By inducing NFeB activation, P. gingivalis promoted IL-1, IL-6 and IL-12p40 production (Figure 2). Of particular interest was the ability of P.gingivalis to induce transcription of the p40 chain, which is shared between the IL-12 and IL-23 molecules and not the p35 chain, which is essential for the formation of functional IL-12p70. In our studies, P. gingivalis appeared to favor MyD88-dependent pathways leading to NFeB activation and p40 transcription over pathways necessary for IRF3 phosphorylation and p35 generation, consistent with the notion that P. gingivalis primarily engages TLR2 related pathways 25 20. This elevated production of IL-12p40 with inhibition of IL-12p35 ultimately restricted formation of the intact IL-12p70 molecule, but allowed for IL-23 production favoring Th17 pathways (Figure 2). In addition we found that promotion of Th17 lineage responses was also aided by P. gingivalis proteases, which appeared to differentially degrade pivotal cytokines. IL-12 was both prevented and degraded by P. gingivalis, whereas IL-1 was more resistant to proteolysis (Figure 2). Therefore, our data implicate multiple pathways by which P. gingivalis may orchestrate Th17-dependent chronic inflammation. Ultimately, we want to evaluate whether disruption Th17 pathways may be an effective treatment for periodontal disease. Currently a number of biologic treatments targeting the differentiation of Th17 cells (e.g. IL-6R, IL-23 inhibitors) are used in autoimmune disorders and as part of our future plans we aim to study the effect on periodontal health/disease in patients receiving relevant treatments. Another way by which we will evaluate the effects Th17 disruption on periodontal stability is studying patients with genetic disruptions in relevant pathways.